Elusive Search for HIV/AIDS Vaccine
New England Journal of Medicine
January 8, 2008
by Robert Steinbrook

In April 1984, when the human immunodeficiency virus (HIV) and Aids were just beginning to be understood, a senior official in the Department of Health and Human Services stated that there would be a marketable vaccine within “a minimum of two years, probably more like three years.”

This prediction has haunted the search for an Aids vaccine, whose most recent setback was the announcement that a promising vaccine candidate, Merck’s V520, was not effective and may actually have increased some subjects’ risk of acquiring HIV. Unfortunately, about a quarter-century after the discovery of HIV, there is neither a marketable vaccine nor a credible expectation about when there will be one.

A successful HIV vaccine would either prevent infection or reduce the viral load in persons who became infected, helping them to remain healthy and perhaps reducing their likelihood of transmitting the virus to others. But vaccine developers face many scientific challenges, including those posed by genetic diversity and rapid changes of the viral envelope proteins and other features that allow HIV to elude immune control.

Critical immunologic responses that would prevent infection or control the virus are incompletely understood. Nonetheless, there has been considerable interest in vaccines, such as V520, that induce primarily T-cell responses, because numerous studies have provided evidence of the role of T-cell immunity in controlling HIV infection.

The V520 vaccine consists of three injections of a recombinant, replication-defective adenovirus type five vector that carries three HIV genes and was designed to elicit HIV-specific T-cell immune responses. Adenovirus type five is a common cold virus and is generally considered harmless.

The HIV Vaccine Trials Network, which is funded by the National Institute for Allergy and Infectious Diseases (NIAID), in conjunction with the vaccine developer, Merck, conducted the STEP trial in the United States and abroad; the Phambili trial was conducted in South Africa.

In September 2007, the STEP trial, which had enrolled 3,000 subjects, was stopped after the data and safety monitoring board, at its first interim analysis, concluded that the vaccine neither prevented HIV infection nor reduced the amount of virus in those who became infected.

In October, the Phambili trial, which had enrolled only 801 subjects, was also stopped; the trial’s monitoring board concluded that there was no reason to anticipate more favourable results. Participants in both studies were told whether they received vaccine or placebo.

Since there was only one HIV case in a female STEP subject (though there were more than 1,100 women enrolled), post hoc analyses of the data have focused on men.

As of October 17, 2007, there had been 49 HIV infections in men who were HIV-seronegative when they underwent randomisation and who had received at least one dose of the vaccine, as compared with 33 infections in comparable men who received placebo.

The men at greatest risk for HIV infection appeared to be those who both received the vaccine and had higher levels of immunity to adenovirus type five before enrolment. Despite the sobering preliminary analyses, it is unclear whether administration of the vaccine actually increased the risk of acquiring HIV.

This will not be known at least until ongoing studies and data analyses are completed — and might remain uncertain indefinitely. Even the preliminary findings, however, have immediate implications for future vaccine trials, particularly a study involving 8,500 patients that had been scheduled to start in the fall of 2007 but is now on hold until at least the summer of 2008.

That trial, known as Partnership for Aids Vaccine Evaluation (PAVE) 100, will test a vaccine strategy developed at the National Institutes of Health (NIH) that has four components: three injections of an HIV DNA vaccine, followed by a single boost with an HIV–adenoviral-vector vaccine.

The multiclade vaccine primarily elicits T-cell immunity and is another important test of the T-cell vaccine concept. The NIH vaccine differs in many respects from the Merck product; notably, it entails one injection of adenoviral vectors, not three, and the other injections are only of DNA plasmids.

However, the vector is also a recombinant, nonreplicating adenovirus type five, although it is missing more genes than V520 and differs structurally from it in some other ways.

The protocol is being intensively reviewed because of safety concerns, according to Gary Nabel, the director of NIAID’s Vaccine Research Center, where the vaccine was developed.

Although no decisions have been made, a redesign of the protocol is under way. For example, it is likely that the initial subjects will have no evidence of prior infection with adenovirus type five.

That requirement might preclude recruitment of subjects at some of the planned sites: in East Africa, as many as 95 per cent of people may have antibodies against adenovirus type five, as compared with less than half of people in the United States.

The only ongoing large study of an Aids vaccine is being conducted in Thailand, where a strategy of “priming” the immune system with a live recombinant canary pox vector containing HIV genes and then “boosting” it with a glycoprotein 120, thereby eliciting both B-cell and T-cell immunity, is being evaluated in 16,400 HIV-negative adults.

The study started in 2003 and is expected to continue until July 2009. When the data safety and monitoring board last met, in July 2007, it recommended that the trial continue. Unless an experimental vaccine turns out to be highly effective in preventing HIV infection, the results of one large phase 2B or phase 3 study are unlikely to lead to its licensure.

A vaccine study that would be considered “successful” is more likely to be one that provides some of the missing information about the specific immune responses that protect against infection and that leads to additional large trials specifically designed to support the licensure of a refined vaccine.

Such additional trials could easily take 5 years or more to complete. In 2005, the global investment in HIV vaccine research and development was estimated at $759 million, of which 88 per cent was from governments, 10 per cent from commercial firms, and 2% from philanthropy. The NIH spends about $600 million a year on researching such vaccines.

Although the STEP trial and others that failed to achieve their desired end points have brought new knowledge, each disappointment also reinforces the view that a licensed Aids vaccine is at least a decade away — and that is if things go well, which has not happened yet.

Meanwhile, individuals and public health officials can only try to prevent HIV transmission through education and behaviour modification, condom use, needle-exchange programs, and other effective, albeit imperfect, means that are already available.

According to Anthony Fauci, the director of the NIAID, “To be brutally honest with ourselves, we have to leave open the possibility . . . that we might not ever get a vaccine for HIV.

People are afraid to say that because they think it would then indicate that maybe we are giving up. We are not giving up. We are going to push this agenda as aggressively and energetically as we always have. But there is a possibility — a clear finite possibility — that that’s the case.”